CZ310997A3 - Taxoids, process of their preparation and pharmaceutical compositions containing thereof - Google Patents

Abstract

Novel taxoids of general formula (I), wherein R is a substituted alkyl radical or an alkenyl, alkynyl, cycloalkyl, optionally substituted cycloalkenyl or phenyl radical, or an optionally aromatic 5- or 6-membered heterocyclic radical; and Z is a hydrogen atom or a radical of general formula (II), wherein R1 is an optionally substituted benzoyl, thenoyl or furoyl radical or a radical R2-O-CO-, where R2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl, or heterocyclyl radical, and R3 is an aromatic heterocyclic, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl or naphthyl radical. The novel products of general formula (I), wherein Z is a radical of general formula (II), have remarkable antitumoral activity.

Description

Taxoids, process for their preparation and pharmaceutical compositions containing these taxoids

The invention relates to novel taxoids of the formula I

in which

R is

a straight or branched alkyl group having 1 to 8 carbon atoms, substituted with a substituent selected from the group consisting of halogen atoms consisting of fluorine, chlorine, bromine and iodine, amino groups and an alkylamino group in which the alkyl radical contains 1 to 4 carbon atoms, dialkylamino- a group in which the alkyl radicals contain 1 to 4 carbon atoms or form, together with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocyclic group optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen atoms; and is optionally substituted with (C 1 -C 4) alkyl or phenyl or phenylalkyl, the alkyl radical of which contains 1 to 4 carbon atoms, carboxy, alkyloxycarbonyl, the alkyl radical of which contains 1 to 4 carbon atoms, cyano, carbamoyl, N-alkylcarbamoyl A group having an alkyl radical of 1 to 4 carbon atoms, a Ν, Ν-dialkylcarbamoyl group in which the alkyl radicals contain 1 to 4 carbon atoms or form, with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocyclic a group optionally containing a second heteroatom selected from oxygen, sulfur and nitrogen atoms and optionally substituted by a C1-C4 alkyl group or a phenyl or phenylalkyl group having a C1-C4 alkyl radical,

straight or branched chain C 2 -C 8 alkenyl, straight or branched C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, said groups they may be optionally substituted with a substituent selected from the group consisting of halogen atoms of fluorine, chlorine, bromine and iodine, amino, alkylamino in which the alkyl radical contains 1 to 4 carbon atoms, dialkylamino in which the alkyl radicals contain 1 to 4 carbon atoms Or, together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocyclic group optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen atoms and optionally substituted with an alkyl group containing 1; 1-4 carbon atoms or a phenyl or phenylalkyl group having an alkyl radical of 1 to 4 carbon atoms, a carboxy group, an alkyloxycarbonyl group having an alkyl radical of 1 to 4 carbon atoms, a cyano group, a carbamoyl group, an N-alkylcarbamoyl group whose alkyl group the radical contains from 1 to 4 carbon atoms, the Ν, Ν-dialkylcarbamoyl group in which the alkyl radicals contain from 1 to 4 carbon atoms or form a saturated 5- or 6- with the nitrogen atom to which they are attached a membered heterocyclic group which optionally contains a second heteroatom selected from oxygen, sulfur and nitrogen atoms and is optionally substituted by a C1-C4 alkyl group or a phenyl or phenylalkyl group having a C1-C4 alkyl radical, or

- a phenyl group or a 5- or 6-membered heterocyclic aromatic group containing as the heteroatom an oxygen atom, a sulfur atom or a nitrogen atom, and

Z is hydrogen or a group of formula II

RjNH 0

Oh in which

R ₁ represents a benzoyl group, which is optionally substituted.

bolded with one or more of the same or different substituents selected from the group consisting of halogen atoms, (C1-C4) -alkyl, (C1-C4) -alkoxy and trifluoromethyl, thenoyl or furoyl or of the formula (III-C) - ^ Ο-, in which R 8 represents

- C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 7 -C 7 -cycloalkyl group These groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, hydroxy, C 1 -C 4 alkoxy, dialkylamino, wherein each alkyl radical contains 1 to 4 carbon atoms. Atoms, piperidino, morpholino, 1-piperazinyl optionally substituted in the 4-position with C1-C4 alkyl or phenylalkyl in which the C1-4 alkyl radical is present, cycloalkyl having 3 and C 6 -C 6 cycloalkenyl, phenyl optionally substituted by one or more substituents selected from halogen, C 1-4 alkyl and C 1-4 alkoxy , cyano, carboxyl and alkoxycarbonyl in which the alkyl radical contains 1 to 4 carbon atoms,

- a phenyl or alpha- or beta-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms,

A 5-membered aromatic heterocyclic group, preferably selected from the group consisting of furyl and thienyl, or

A 4- to 6-membered saturated heterocyclic group which is optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms / represents a straight or branched alkyl group having 1 to 8 carbon atoms, a straight or branched alkenyl group having 2 to 8 carbon atoms straight or branched (C 2 -C 8) alkynyl, (C 3 -C 6) cycloalkyl, phenyl or alpha or beta-naphthyl optionally substituted by one or more substituents selected from halogen, alkyl a group, an alkenyl group, an alkynyl group,

aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amio , alkylamino, dialkylamino, carboxyl, alkylcarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, or a 5-membered aromatic heterocyclic group containing one or more of the same or different heteroatoms selected from nitrogen, oxygen and sulfur atoms and optionally substituted by one or more of the same or different substituents selected from the group consisting of halogen atoms, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylka ronyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkoxycarbonyl, alkoxy, aryloxy and acylamino, wherein in the substituents phenyl or alpha or beta-naphthyl and aromatic heterocyclic groups the alkyl groups and the alkyl radicals of the other groups contain 1 to 4 carbon atoms and the alkenyl and alkynyl groups contain up to 8 carbon atoms and the aryl groups are phenyl or alpha or beta-naphthyl groups.

Among the compounds described in the prior art are those described in French Patent FR 2 698 871 having a cyclopropyl group at the 7-8 position and having either a hydroxyl group or an acetyl group at position 10, the remaining substituents being the same as the substituents of the compounds according to the invention.

- 5a

U.S. Pat. No. 5,254,580 discloses compounds bearing at the 7-8 position a cyclopropyl group and at the 10 position a -OCOR, -OCOOR, H, OH or CO group. All of these compounds are different from the compounds of the invention.

Preferably, aryl groups R ve are phenyl or alpha or beta-naphthyl groups optionally substituted by one or more substituents selected from fluorine (chlorine, bromine or iodine), alkyl, alkenyl group, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arythio, hydroxy, hydroxySUBSTITUTE SHEET 5, alkyl, mercapto, formyl , acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkyl and dialkylcarbamoyl, cyano, nitro a trifluoromethyl, the alkyl groups and the alkyl radicals of the other groups having 1 to 4 carbon atoms, the alkenyl and alkynyl groups having 2 to 8 carbon atoms and the aryl groups being phenyl or alpha or beta-naphthyl groups.

Preferably, heterocyclic groups within the meaning of the general substituent are 5-membered aromatic heterocyclic groups containing one or more identical or different atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms and optionally substituted with one or more identical or different substituents selected from the group consisting of halogen atoms (atom) fluorine, chlorine, bromine and iodine), (C 1 -C 4) alkyl, (C 6 -C 10) aryl, (C 1 -C 4) alkoxy, (C 6 -C 10) aryloxy, amino group C 1-4 alkylamino, dialkylamino in which each alkyl radical contains 1 to 4 carbon atoms, acylamino in which the acyl radical contains 1 to 4 carbon atoms, alkoxycarbonylamino in which the alkoxy radical contains 1 to 4 carbon atoms 4 carbon ato we, an acyl group having 1 to 4 carbon atoms, an arylcarbonyl group having an aryl radical having 6 to 10 carbon atoms, a cyano group, a carboxy group, a carbamoyl group, an alkylcarbamoyl group having an alkyl radical having 1 to 4 carbon atoms, a dialkylcarbamoyl group in which each alkyl radical contains 1 to 4 carbon atoms, or an alkoxycarbonyl group in which the alkoxy radical contains 1 to 4 carbon atoms.

In particular, the invention relates to compounds of formula I wherein Z is hydrogen or a group of formula

φφ

ΦΦΦ • φ φ φ φ φ φφ

II wherein R represents a benzoyl radical or a radical R ₂ -O-CO- in which _R2 represents a tertbutyl radical and R represents an alkyl group containing 1-6 carbon atoms, alkenyl group having 2-6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group optionally substituted by one or more identical or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom), alkyl group (methyl group), alkoxy group (methoxy group) ), dialkylamino (dimethylamino), acylamino (acetylamino), alkoxycarbonylamino (t-butoxycarbonylamino) and trifluoromethyl, or 2-furyl or

3-furyl or 2-thienyl or 3-thienyl or 2-thiazolyl or 4-thiazolyl or 5-thiazolyl and R represents a (C 3 -C 6) cycloalkyl or phenyl, 2-pyridyl, 3 -pyridyl group,

4-pyridyl, 2-furyl, 3-furyl,

2-thienyl or 3-thienyl.

In particular, the invention further relates to compounds of formula I wherein Z is hydrogen or a group of formula II wherein R 1 is benzoyl or R ₂ -O-CO- wherein R ₂ is tert-butyl and R ^ is isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl,

2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl and R is cyclopropyl, cyclopentyl, phenyl, 2-pyridyl, 2-thienyl or 2-furyl .

Compounds of formula I in which Z is a group of formula II have remarkable anti-tumor and anti-tumor activity.

leukemic properties.

The compounds of the formula I in which Z represents a group of the formula II can be obtained according to the invention by esterification of a compound of the formula III

wherein R 6 and R 6 are as defined above and either R 8 is a hydrogen atom and is a hydroxy function or R 8 and R 8 together form a saturated 5- or 6-membered heterocycle, using an acid of formula IV

R-CO-OH (IV) in which R is as defined above, or a derivative thereof, such as a halide, symmetrical anhydride or mixed anhydride, to form a compound of formula V

in which R,

R 6, R 8 and R 8 have the meanings given above and then replace the protecting groups R? or Rg and R? hydrogen atoms.

The esterification using an acid of formula IV can be carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activating agent (aminopyridines) in an organic solvent (ether, ester, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at between -10 and 90 ° C.

The esterification can also be carried out using an acid of formula IV in the form of a symmetrical anhydride, working in the presence of an activating agent (aminopyridines) in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons). temperature between 0 and 90 ° C.

The esterification can also be carried out using an acid of the formula IV in the form of a halide or mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base (tertiary aliphatic amine), working in an organic solvent (ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) and at a temperature between 0 and 80 ° C.

When R 8 is hydrogen, R 6 is preferably methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, beta-trimethylsilylethoxymethyl, benzyloxycarbonyl or tetrahydropyranyl.

When R 8 and R 8 together form a heterocyclic group, the heterocyclic group preferably consists of an oxazolidine ring which is optionally mono-substituted.

or gem-disubstituted at position 2.

Replacement of protecting groups in the meaning of the general substituents R? or / and Rg and R? depending on the nature of these protecting groups, the hydrogen atoms may be as follows:

1) when Rg represents a hydrogen atom and R6 represents a hydroxy function, the replacement of the protecting groups by hydrogen atoms is carried out using a mineral acid (hydrochloric acid, sulfuric acid, hydrofluoric acid) or an organic acid (acetic acid, acid) methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid), used alone or in a mixture, working in an organic solvent selected from the group consisting of alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons or nitriles, and temperature between -10 and 60 ° C

2) when R and R _g together form a 5- or 6-membered saturated heterocyclic ring and especially an oxazolidine ring of general formula VI

MyO

Rg Rg (vi) wherein R6 is as defined above, and Rg and Rg, which are the same or different, represent a hydrogen atom or a (C1-C4) alkyl group or an aralkyl group in which the alkyl residue contains 1 to 4 carbon atoms atoms and the aryl radical preferably represents a phenyl group optionally substituted by one or more alkoxy groups containing 1 to 4 carbon atoms, or an aryl group preferably representing a phenyl group optionally substituted by one or more alkoxy groups containing 1 to 4 carbon atoms Or either R _o is C 4-C nebo alkoxy or trihalomethyl, such as trichloromethyl, or phenyl optionally substituted by trihalomethyl, such as trichloromethyl, and Rg is hydrogen or R _g and R 8 together with the carbon atom to which they are attached form it is attached, a 4- to 7-membered ring, replacement of the protective group formed by _R 'and R_ 7 hydrogen atoms is performed, depending on the meanings of the substituents R _1, R _g and R as follows:

a) when R ₁ represents a tert-butoxycarbonyl radical, Rg and Rg are the same or different, znamenajíH or an alkyl radical or an aralkyl (benzyl) or aryl group (phenyl group), or either _of R znaO names trihalomethyl or a phenyl radical substituted with a trihalomethyl radical and Rg represents a hydrogen atom, or R _g and R g together form a 4- to 7-membered ring, treatment of the ester of formula V with a mineral or organic acid, optionally carried in an organic solvent such as an alcohol, leads to the compound of formula VII

(VII) OCOC ₆ H ₅ wherein R _g is as defined hereinbefore, which is then acylated using benzoyl chloride in which the phenyl ring is optionally substituted, thenoyl chloride, furoyl chloride or a compound of formula VIII • · · · · • · · · · _ 12 _ ·································

R ₂ -O-CO-X (VIII) in which R ₂ has the abovementioned meaning and X represents a halogen atom (fluorine, chlorine) atom or a residue ^not -0- ^ ^ ° -O-CO-OR ₂ 'to give a compound of formula I wherein Z is a group of formula II.

Preferably, the compound of formula V is reacted with formic acid at a temperature near 20 ° C to form a compound of formula VII.

Preferably, the acylation of a compound of formula VII with benzoylchloride in which the phenyl group is optionally substituted, thenoyl chloride or furoyl chloride or a compound of formula VIII is performed in an inert organic solvent selected from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate, and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane in the presence of a mineral base such as sodium bicarbonate or an organic base such as triethylamine. This reaction is carried out at a temperature between 0 and 50 ° C, preferably at a temperature close to 20 ° C.

b) when R 1 is an optionally substituted benzoyl, thenoyl or furoyl group or R ₂ O-CO-, in which R ₂ is as defined above, R 8 is a hydrogen atom or a C 1 -C 4 alkoxy group or a phenyl group substituted by one or more alkoxy groups having from 1 to 4 carbon atoms and R 8 represents a hydrogen atom, then the replacement of the protecting group consisting of the general substituents R 8 and R 8 is replaced by a hydrogen atom; The hydrogen atoms are carried out in the presence of a mineral acid (hydrochloric acid, sulfuric acid) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid), which is used alone or in a mixture in stoichiometric or catalytic amounts, an organic solvent selected from the group consisting of alcohols, ethers, esters, aliphatic;

hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons, and at a temperature between -10 and 60 ° C, preferably at a temperature between 15 and 30 ° C.

Compounds of formula III may be obtained under the reaction conditions described in PCT International Application WO 94/13654.

Compounds of formula III may also be obtained by esterifying a baccatin III derivative of formula IX

using an acid of formula X

Ο-ΐς wherein R _1, R, R _g and R, are as defined above, or a derivative of this acid such as a halide, the symmetrical anhydride or a mixed anhydride, and subsequent replacement of the acetoxy radical at position 10 by a hydroxyl radical.

The esterification is carried out under conditions analogous to those described above for the esterification of a compound of formula III using an acid of formula IV.

• «

The replacement of the acetoxy group at the 10-position with a hydroxy group is generally carried out using zinc iodide.

The compound of formula IX can be obtained under the conditions described in PCT International Application WO 94/13654 by treatment of 2alpha-benzoyloxy- with alkali metal halide (sodium iodide, potassium fluoride) or alkali metal azide (sodium azide) or quaternary ammonium salt or phosphate of alkali metal. 4alpha, 10beta-diacetoxy-1 beta, 13alphadihydroxy-5beta, 20-epoxy-7beta-trifluoromethylsulfonyloxy-9-oxo-11-taxene.

Compounds of formula I in which Z is a group of formula II may also be obtained by esterification of a compound of formula XI

wherein R is as defined above, using an acid of formula X or a derivative thereof, such as a halide, symmetrical anhydride or mixed anhydride, to form a compound of formula V wherein R-, Rg- and Rg-protecting groups are replaced by atoms hydrogen under the conditions described above.

Compounds of formula XI, i.e. compounds of formula I in which Z is hydrogen, can be obtained by esterification of a compound of formula XII

wherein Z is a hydroxy-protecting group such as a silylated group, especially a triethylsilyl group, using an acid of formula IV or a derivative thereof such as a halide, symmetrical anhydride or mixed anhydride, under the conditions described above for esterifying the compound of formula III using an acid of formula (IV) or a derivative thereof and subsequently replacing the protecting group Z with a hydrogen atom under conditions that do not affect the rest of the molecule.

The compound of formula (XII) may be obtained under the conditions described in PCT International Application WO 94/13654.

The novel compounds of the formula I obtained by carrying out the processes according to the invention can be purified by methods known per se, such as, in particular, crystallization or chromatography.

Compounds of formula I wherein Z is a group of formula II have remarkable biological properties.

In vitro measurement of biological activity is performed on tubulin extracted from pig brain by the method of M. L. Schlanski et al., Proc.Nati.Acad.Sci. USA, 70, 765-768 (1973). The study of the depolymerization of microtubules to tubulin is performed according to the method of G. Chauviere et al., C.R.Acad.Sci293, Series II, 501503 (1981). In this study, compounds of formula I in which Z is a group of formula II have been shown to be at least as active as taxol or

Taxoter.

• fl • · ····

Fl flf fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl fl

In vivo tests have shown that compounds of formula I wherein Z is a group of formula II are effective in B16-grafted melanoma mice at intraperitoneal doses of between 1 and 10 mg / kg, and are also effective for other liquid or solid tumors.

The novel compounds of the invention have antitumor properties and are particularly effective against tumors that are resistant to taxol or Taxotere. Such tumors include colon tumors that have overexpression of the mdr 1 gene (global drug resistance gene). Global drug resistance is an expression that refers to tumor resistance to different drugs having different structures and different mechanisms of action. Taxoids are known to be well recognized by experimental tumors such as P388 / DOX, a cell line selected for its resistance to doxorubicin (DOX), which expresses said mdr 1 gene.

In the following, the invention will be further elucidated by means of examples of specific embodiments thereof, which are illustrative only and are not intended to limit the scope of the invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of 62 mg of 2-pyridinecarboxylic acid in 25 cm ^{3 of} anhydrous acetic anhydride, maintained under an argon atmosphere, 380 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy- 1 beta, 10-betadihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19-nor11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) 4-phenyl-1, 3-oxazolidine-5-carboxylate, 25 mg 4-dimethylaminopyridine, 0.5 g molecular sieves 4 ' and 151 N, N'-dicyclohexylcarbodiimide. The reaction mixture is kept under stirring at a temperature in the region of 20 DEG C. for 16 hours, at which time 20 mg of 2-pyridinecarboxylic acid, 8 mg of 4-dimethylaminopyridine,

100 mg of 4Ž molecular sieve and 50 mg of N, N'-dicyclohexylcarbodiimide were added and the reaction mixture was stirred again for 4 hours. The reaction mixture was then filtered through a Celite-lined glass frit. The glass frit is washed with 100 cm @ 3. ethyl acetate, the filtrates are combined, washed successively with 15 cm @ 3 of ethyl acetate. saturated aqueous sodium bicarbonate solution and 5 times 10 cn each. distilled water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (0.27 kPa) at 40 ° C.

715 mg of a white, fragile product are obtained, which product is purified by chromatography on 40 g of silica gel (0.04-0.063 mm) contained in a 2 cm column, eluting with a 99/1 mixture of dichloromethane and methanol, and 10 cm fractions were collected. Fractions containing only the desired product are combined and concentrated to 3 dryness under reduced pressure (0.27 kPa) at 40 cm.

297 mg of (2R, 4S, 5R) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8-betamethylene-9-oxo-10beta- (2-pyridylcarbonyl) oxy-19-nor- 11-Taxen-13-alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

290 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-10beta (2-pyridylcarbonyl) -19-nor-11-taxen13alpha-yl-3 -terc.butoxykarbo:

2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate was dissolved in 5.7 cm @ 3 of a 0.1N ethanolic hydrochloric acid solution. The solution thus obtained is stirred for one hour at a temperature in the region of 20 DEG C. and then concentrated to dryness under reduced pressure (0.27 kPa) at a temperature in the vicinity of 40 DEG C.

The solid residue is dissolved in 50 cm @ 3 of dichloromethane and the solution obtained is washed successively with 2.times.3 cm @ 3 of dichloromethane. saturated

Aqueous sodium bicarbonate solution and then three times with 5 cm each of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

270 mg of a white, brittle product are obtained, which product is purified by chromatography on 30 g of silica gel (0.04-0.063 mm) contained in a 2 cm column, eluting with a 99/1 mixture of dichloromethane and methanol, and 10 cm fractions were collected. Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 20 ° C.

There was thus obtained 189 mg of (2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene 9-oxo-10beta- (2-pyridylcarbonyl) oxy-19-nor-3 -11-Taxen13alpha-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 = -24 (c = 0.52, methanol). @ 1 H-NMR spectral:

(300 MHz, CDCl ^, delta chemical shifts in ppm, coupling constants in Hz)

1.28 (s, 9H: --C (CH3) _3); 1.41 (s, 3H: _--CH3 at position 16 netol7); 1.44 (mt, 1H: --H at position 7); 1.57 (s, 3H: _--CH3 at tol7 = 16n); 1.69 and 2.25 (respectively dd and mt, J = 6 and 5.5, IH each; _--CH2 - ^{at position} 19) 1.89 (s, H: OH at position 1); 1.92 (s, 3H: _-CH3); 2.11 and 2.50 (respectively broad d. And dt, J = 16 and J = 16 and 4.5 Hz, IH _{each, --CH2} - in 6); 2.25 and 2.39 (2 mt, H _{each: --CH2} - at position 14); 2.40 (s, 3H, -COCH _3); 3.29 (mt, 1H: --OH at position 2 '); 4.04 and 4.32 (2 d, J = 9, H each: _--CH2 - at position 20); 4.15 (d, J = 7.5, 1H: --H3); 4.62 (mt, 1H: --H at position 2 '); 4.74 (d, J = 4.5, 1H: --H at position 5); 5.28 (broad d, J = 10, 1H: --H at position 3 '); 5.35 (d, J = 10, 1H: - CONH-); 5.61 (d, J = 7.5, 1H: --H at position 2); 6.28 (broad t, J = 9, 1H: --H at position 13); 6.64 (s, 1H: --H at position 10); 7.25 and 7.45 (mt, 5H: --CH3 at position 3 '); 7.51 [(mt, 3H:

-OCOC ₆ H ₅ (-H at 3 and H at 5) -C 5 H 4 N (-H at 5)]; 7.60 [(t, J = 7.5, 1H):

• · · · · · · · · · · · · · · ·

_{--OCOC6 H5} (--H at position 4)]; 7.85 [(dt, J = 8 in 1,5, 1H: -C5H4N (-H at position 4)]; 8.11 [(d, J = 8, 1H: -C5H4N (-H at position 3)]; 15 [(d, J = 7.5,2H: _{--OCOC6 H5} (--H at position 2 and H at position 6)]; 8.80 [(broad d. J = 4.5, 1H: -C5H4N (- H in 6)].

(2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta, 10-betadihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19-nor11-taxen-13alpha-yl-3- tert-butoxycarbones of 1-2- (4-methoxyphenyl) 4-phenyl-1,3-oxazolidine-5-carboxylate can be prepared as follows:

To a solution of 5.5 g of (2R, 4S, 5R) -2alpha-benzoyloxy-4alpha, 10beta-diacetoxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11- taxen-13alpha-γ-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate in 200 cm @ 2; of anhydrous methanol, maintained under an argon atmosphere, is added with stirring at a temperature in the region of 20 DEG C., 20 g of molecular sieve 4 in powder form and 9.3 g of zinc iodide. The reaction mixture is maintained under stirring for 3 days at a temperature in the region of 20 DEG C., then 3.72 g of zinc iodide and 4 g of molecular sieve are added and stirring is continued for 24 hours at a temperature in the region of 20 DEG.

The reaction mixture was filtered through a Celite pad. The glass frit is then washed with 100 cm @ 3 of dichloromethane and the filtrates are combined and poured into 200 c of distilled water. The biphasic mixture is stirred for 30 minutes, then the aqueous phase is separated by decantation and reextracted three times with 200 cm @ 3 of dichloromethane. The organic phases are combined, washed with 50 cm @ 3. distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

5.3 g of a white, fragile product are obtained which is purified by chromatography on 160 g of silica gel (0.04-0.063 mm) contained in a column of 3.8 cm diameter, eluting with a dichloromethane / methanol mixture.

• it • · • ·· • ·· • It does it • it • it • · • · this - 20 - • it »·· • • to ·· a 99: 1 ratio and collecting fractions of volume 100 ALIGN! 3 cm Fractions containing only the desired the product merges and concentrate to dryness under reduced pressure (0.27 kPa) at temperature

··· · · ° C.

3.7 g of a white, fragile product are obtained, which product is purified by chromatography on 175 g of silica gel (0.04-0.063 mm) contained in a column of 3.8 cm diameter, eluting with a mixture of dichloromethane and methanol in a volume ratio. 99.6: 0.4 and collect 50 ck fractions? .

Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

There was thus obtained 1.78 g of (2R, 4S, 5R) -4alpha-acetoxy2alpha-benzoyloxy-1beta, 10beta-dihydroxy-5beta, 20-epoxy7beta, 8beta-methylene-19-nor-11-taxen-13alpha-yl-3. tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

(2R, 4S, 5R) -2alpha-Benzoyloxy-4beta, 10beta-diacetoxy5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo19-nor-11-taxen-13alpha-yl-3-tert. butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate can be prepared as follows:

To a solution of 4.01 g of (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid in 190 cm? of anhydrous ethyl acetate maintained under an argon atmosphere, 4.75 g of 2alpha-benzoyloxy-4alpha, 10beta-diacetoxy-1 beta, 13alpha-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene are added with stirring at a temperature close to 20 ° C. -9-oxo-19-nor-11-taxene, 05 g of 4-dimethylaminopyridine and 3.01 g of N, N'-dicyclohexylcarbodiimide. The reaction mixture is kept under stirring for 2 hours at a temperature in the region of 20 DEG C. and then filtered through a glass frit lined with celite. Glass frit • · • h

It is then washed twice with 50 cm ^{3 of} ethyl acetate each, and the filtrates are combined, washed five times with 50 cm ^{3 of} distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

9.67 g of a yellow, brittle product are obtained, which is taken up in 70 cm @ ^{3 of} diisopropyl ether. The suspension obtained is stirred for one hour at a temperature in the region of 20 cm ³ and then filtered through a glass frit. The glass frit is then washed twice with 20 cm ^{3 of} diisopropyl ether each time, and the filtrates are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

8.09 g of a yellow, brittle product are obtained, which product is purified by chromatography on 250 g of silica gel (0.0630.2 mm) contained in a column of 3.8 cm diameter, eluting with a dichloromethane / methanol mixture (v / v). 99: 1 and 100 cm ³ fractions were collected. Fractions containing only the desired product are combined and concentrated under reduced pressure (0.27 kPa) at 40 ° C.

There was thus obtained 7.23 g of (2R, 4S, 5R) -2alpha-benzoyloxy4alpha, 10beta-diacetoxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxene. 13-alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

(2R, 4S, 5R) -3-tert-Butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylic acid can be prepared as follows:

A solution of (2R, 3S) -methyl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 0.25 g of pyridinium p-toluenesulfonate in 200 cm ^{3 of} toluene is dehumidified by distilling off 20 cm ^{3 of} solvent. 6.34 cm @ ^{3 of} p-methoxybenzaldehyde dimethyl acetal are added over a period of 5 minutes and the reaction mixture is heated to boiling.

O · · ···· · · · · · · · · · · · · · · · · · · · · · ·

During the addition, 50 cm ^{3 of} solvent are distilled off and then 100 cm ^{3 of} solvent are distilled off. After cooling to a temperature in the region of 20 DEG C., 80 cm @ ^{3 of} cyclohexane are added over 10 minutes. The reaction mixture was cooled to 0-5 ° C. The suspension obtained is filtered through a glass frit and the filter cake obtained is washed with 40 cm @ ^{3 of} cyclohexane and then dried under reduced pressure at a temperature in the region of 20 DEG.

Thus, 10.39 g of (2R, 4S, 5R) 3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-5-methoxycarbonyl-1,3-oxazolidine having the following characteristics are obtained in 74% yield. :

Infrared spectrum (in KBr tablet):

characteristic absorption bands at:

3100-3000, 2980, 2960, 2930, 2910, 2840, 1740, 1700, 1614, 1514, 1460, 1435, 1390, 1370.1245, 1175, 1165, 816, 760 and 700 ^{cm-1 1} H-NMR :

(400 MHz, CDCl-j, temperature: 323 ° K, delta chemical shifts in ppm, coupling constants in Hz)

Hz): 1.11 (s, 9H); 3.60 (s, 3H); 3.82 (s, 3H); 4.58 (d, J = 5, 1 H); 5.42 (broad d, J =

5, 1H); 6.38 (broad s, 1H); 6.92 (d, J = 7.5, 2H); 7.30 and 7.45 (mt, 7H).

14 cm @ 3 of an aqueous solution containing 0.31 g of lithium hydroxide monohydrate are added to a solution of 3.0 of the product obtained in the preceding 3-, 3-step in 27 cm of methanol. The mixture was stirred for two hours at a temperature near 20 ° C. Methanol was removed by distillation under reduced pressure, then 40 tin dichloromethane was added. Under vigorous stirring, the mixture is acidified by adding 1N hydrochloric acid to pH 1. After decantation, the aqueous phase is extracted twice with 40 cm ^{3 of} dichloromethane each time. The combined organic phases were dried over sodium sulfate. After filtration and evaporation of the solvent, 2.88 g of acid 9 are obtained in a yield of 94.5%

9 9

9 9

9 9 9

9

9 (2R, 4S, 5R) -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-3, 3-oxazolidine-5-carboxylic acid having the following characteristics:

Infrared spectrum (in KBr tablet):

characteristic absorption bands at:

3325-2675, 2980, 2955, 2935, 2845, 1755, 1700, 1615, 1590, 1515, 1460, 1250, 1175, 1030, 835, 765, and 705 cm -1 ¹ H NMR spectrum:

(250 MHz, CDCl3, delta chemical shifts in ppm, coupling constants in Hz) 1.08 (s, 9H);

3.82 (s, 3H); 4.61 (d, J = 5, 1 H); 5.42 (broad d, J = 5, 1H); 6.38 (broad s, 1H); 6.92 (d, J = 7.5, 2H); 7.30 and 7.45 (mt, 7H).

The 2alpha-benzoyloxy-4alpha, 10beta-diacetoxy-1 beta, 13alphadihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19-nor11-taxene can be prepared as follows:

To a solution of 3.85 g of 2alpha-benzoyloxy-4alpha, 10beta-diacetoxy-1 beta, 13alpha-dihydroxy-5beta, 20-epoxy-9-oxo-7-betatrifluoromethylsulfonyloxy-11-taxene in a mixture of 75 cn? of acetonitrile and 7.5 cm @ 3 of anhydrous tetrahydrofuran, maintained under an argon atmosphere, are added, with stirring, at a temperature in the region of 20 DEG C., 1.9 g of molecular sieve 4 in powder form and 5.8 g of sodium chloride. The reaction mixture is stirred for 30 minutes at a temperature in the region of 20 DEG C. and then heated to reflux (75 DEG C.) and held at that temperature for 2.5 hours. After cooling to a temperature in the region of 20 DEG C., the reaction mixture is filtered through a glass frit. The glass frit is then washed three times with 80 cm 3 each. The combined filtrates are washed successively with 25 ml of dichloromethane. of saturated aqueous sodium bicarbonate solution and twice each with 25 cn? distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

• 9

9

9 · 9

3.5 g of a white, fragile product are obtained, which product is purified by chromatography on 140 g of silica gel (0.0630.2 mm) contained in a 3.5 cm column, eluting with a dichloromethane / methanol mixture (v / v). 99: 1 and collecting 50 cn fractions? . Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

2.7 g of 2α-benzoyloxy-4α, 10-betadiacetoxy-1, beta, 13α-dihydroxy-5β, 20-epoxy-7β, 8-betamethylene-9-oxo-19-nor-11-taxene are thus obtained in the form of a white, brittle product.

2alpha-Benzoyloxy-4alpha, 10beta-diacetoxy-1 beta, 13alphadihydroxy-5beta, 20-epoxy-9-oxo-7beta-trifluoromethylsulfonyloxy-11-taxene can be prepared as follows:

To a solution of 0.59 g of 2alpha-benzoyloxy-4alpha, 10beta-diacetoxy-5beta, 20-epoxy-9-oxo-1beta, 7beta, 13alpha-trihydroxy-11-taxene (baccatin III) in 50 cn? of dichloromethane, maintained under an argon atmosphere, is added with stirring at a temperature in the region of 20 DEG C. at 0.32 cm @ 3. of anhydrous pyridine and then dropwise at a temperature in the region of 20 DEG C. 0.25 cm @ 3. trifluoromethanesulfonic anhydride. The reaction mixture was then heated at reflux (40 ° C) for three hours and then 0.08 cm 3. trifluoromethanesulfonic anhydride and refluxing is continued for one hour. After cooling to a temperature in the region of 20 DEG C., the reaction mixture is poured into a mixture of 50 cm @ 3. dichloromethane and 20 cn? distilled water. The organic phase is separated by decantation, washed successively with 10 cm @ 3

1N aqueous hydrochloric acid solution and twice 10 cn? distilled water, dried over magnesium sulphate, filtered, and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

0.75 g of a white, fragile product is obtained, which is · 9 · 99 ♦ ··

99 99 9 999

9 9 9 9 9

9 9 9 9 9 • »99 999 9

9

The residue is purified by chromatography on 60 g of silica gel (0.063-0.2 mm) contained in a 2.5 cm column, eluting with a dichloromethane / methanol mixture (98.5: 1.5 by volume) and Do fractions of 20 cn are collected? .

Fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C.

0.675 g of 2alpha-benzoyloxy-4alpha, 10beta-diacetoxy-1beta, 13alpha-dihydroxy-5beta, 20-epoxy-9-oxo-7beta-trifluoromethylsulfonyloxy-11-taxene are obtained in the form of a white brittle product.

2alpha-Benzoyloxy-4alpha, 10beta-diacetoxy-5beta, 20-epoxy9-oxo-1beta, 7beta, 13alpha-trihydroxy-11-taxene (baccatin III) can be prepared as follows:

To a solution of 293.9 g of 10-desacetylbaccatin III in 2.7 l of pyridine was added 182 g of triethylsilyl chloride over 1 hour and 20 minutes. The resulting solution was stirred for 40 hours at 5 ° C. 360 g of acetic anhydride are then added, maintaining the temperature of the reaction mixture at 5 ° C. The suspension obtained is stirred for 48 hours at 20 DEG C. and then poured into 40 liters of ice water. The precipitate formed is collected by filtration and then washed eight times with 2 liters of water and finally dissolved in 3 liters of ethyl acetate. The organic phase is dried over magnesium sulphate.

After filtration and concentration to dryness, the product obtained is crystallized from diisopropyl ether.

There was thus obtained 7-triethylsilylbaccatin II in 77% yield, having the following characteristics: melting point: 254 [deg.] C., .beta.-nuclear magnetic resonance spectrum:

(400 MHz, CDClg, delta chemical shifts in ppm) φ · · ·

Φ Φ • φ * Φ φ φ φφφφ Φ • Φ • Φ • φφφ • Φ φ · • w * · • · · φ Φ Φ Φ φ Φ • φ φ • Φ ·· · ·· »· ΦΦ φφ ♦

- 26 0.58 (mt, 6Η: ethyl CH ₂ ; 0.92 (t, J = 7.5 Hz, 9H: ethyl CH ₃ ; 1.02 (s, 3H: CH ₃ ); 1.18 (s) , 3H: _CH3); 1.68 (s, 3H: _CH3); 1.75 (broad s., 1H: OH at position 1); 1.87 and 2.53 (2 mt, 1H each.; CH ₂ 6); 2.18 (s, 6H: _CH3 and _ΟΟΟΗ β); 2.27 (mt, 2H: _CH2 at position 14); 2.28 (s, 3H: _COCH3); 2.47 ( broad, 1H: OH at position 13), 3.88 (d, J = 7 Hz, 1H: H3), 4.13 and 4.30 (2d, J = 8.5 Hz, 1H of the product: CH) ₂ at position 20); 4.50 (dd, J = and 7 Hz, 1H: H at. 7); 4.81 (mt, 1H: H at position 13); 4.95 (broad d. J = 10 Hz 1H: H at position 5.63 (d, J = 7 Hz, 1H: H2) 6.46 (s, 1H: H at position 10) 7.46 (t, J = 8.5 Hz) , 2H: _{--OCOC6 H5} H at the meta position.); 7.60 (t, J = 8.5 Hz, 1H: _{--OCOC6 H5} H at para.); 8.10 (d,

J = 8.5 Hz, 2H: _{--OCOC6 H5} H at ortho position).

To a solution of 350 mg of 7-triethylsilylbaccatin III in 3

2.3 cm @ 3 of acetonitrile and 2.4 cm @ 3 of pyridine were added 2.3 g of trifluoroacetic acid. The mixture was stirred at 50 ° C for 48 hours. After cooling, the reaction mixture was taken up in 50 ml. methylene chloride, washed twice with 5 cm ^{3 of} distilled water each, cn? 1N hydrochloric acid and twice each 5 cn? distilled water and dried over magnesium sulfate. Filtration and concentration to dryness under reduced pressure yielded 330 mg of product which was purified by chromatography on 30 g of silica gel contained in a 2 cm column using a 99: 1 mixture of methylene chloride and methanol as eluent. The first 300 cn? The eluate was discarded. Subsequent 275 cm @ 3 gave, after concentration to dryness, 235 mg of baccatin III as a white, brittle product. The yield of this product was 83%.

Example 2

The procedure is as in Example 1, but starting from 270 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy 1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo. 19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and < tb > F-9 * and 46 mg of 2-thiophenecarboxylic acid to give 230 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta-hydroxy-7beta, 8beta -methylene-9-oxo-10-beta- (2-thienylcarbonyl) oxy-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-4- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidin-5- carboxylate.

The procedure is as in Example 1, but starting from 225 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-10beta. - (2-thienylcarbonyl) oxy-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine 5-carboxylate to give 151 mg ( 2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8betamethylene-9-oxo-10beta- (2-thienylcarbonyl) oxy-19-nor-11-taxen13alpha-yl-3- t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ ₂₀ = -23 (c = 0.5, methanol); @ 1 H-nuclear magnetic resonance spectrum:

(300 MHz, CDClg, Delta chemical shifts in ppm, Coupling constants in Hz)

1.27 (s, 9H: --C (CH3) _3); 1.32 (s, 3H: _--CH3 at position 16 or the encapsulating at I7); 1.39 (s, 3H: _--CH3 at position 17 in Lona); 1.43 (mt, 1H: --H at position 7); 1,70 a

2.27 (respectively dd amt, J = 6.5 and 5, 1H each: --CH2 - at position 19); 1.89 (s, 1 H:

-OH v.1); 1.91 (s, 3H: _CH3); 2.13 and 2.48 (broad d respective-. And dt, J = 16 and J = 16 and 4.5, 1H Kazaa _one -CH ₂ - in 6); 2.25 and 2.39 (respectively · dd and nt, J =

15,5 et 9, 1H Joza: _--CH2 - at position 14); 2.39 (s, 3H, -COCH _3); 3.28 (mt, 1H: --OH at 2j; 4.05 and 4.33 (2 d, J = 9, 1H each /: _--CH2 - at position 20); 4.14 (d, J = 7, 5.72 (dt, J = 4.5, 1H: --H at position 5); , J = 10,

1H: --H at position 3; 5.37 (d, J = 10, 1H: - CONH-); 5.72 (d, J = 7.5, 1H: --H at position 2); 6.30 (broad t, J = 9, 1H: --H at position 13); 6.52 (s, 1H: --H at position 10); 7.15 [(dd, J = 5 and 3.5, 1H: H ₄ -C ₃ S (--H. 4)]; from 7.25 * 7.45 (mt, 5H: -C ^ 3J 7.51 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3a H v.5)]; 7.61 [(t, J = 7,5,1H - OCOC ₆ H ₅ (-H v. 4)]; 7.62 [(dd, J = 5 and 1.5, 1H: -C ₄ H ₃ S (-H v. 5)]; 7.88 [( dd, J = 3.5 and 1.5, 1H: H ₃ C ₄ (--H at position. 3)]; 8.15 (d, J = 7.5, 2H: _{--OCOC6 H5} (- H in 2a H in 6).

* · * * * · · *

Example 3

The procedure is as in Example 1, but starting from 270 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19- nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 3

0.038 cm @ 3 of cyclopentanecarboxylic acid gave 187 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta-cyclopentylcarbonyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-11 -taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure is as in Example 1, but starting from 182 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-10beta-cyclopentylcarbonyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene. -9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine

5-carboxylate to give 100 mg of (2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-10beta-cyclopentylcarbonyloxy-5beta, 20-epoxy1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen13alpha. γ-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 ⁼ " 40 (c = 0.5, methanol), .delta.-nuclear magnetic resonance spectrum:

(300 MHz, CDClg, delta chemical shifts in ppm, coupling constants in Hz)

1.26 (s, 3H: _--CH3 at. Ions at 17); 1.29 (s, 3H):

-CH ₃ at 16 or v17); 1.29 (s, 9H: --C (CH3) _3); 1.40 (mt, H: --H at position 7); from l 50do 1.80 [(mt, 4H: -C5H9 (-CH ₂ -CH ₂ 3 4), and H _--CH2 - at position 19) ]; 1.86 (s, 4H:

-CH ₃ and-OH 11) _: cd 1.85 <2.05 [(mt, 4H: -C 5 H 9 (-CH ₂ in 2 and -CH ₂ in 5)];

2.11 et 2.47 (respectively broad d. A. Dt, J = 16 and J = 16 and 4.5, H each: _--CH2 at position 6); 2.22 and 2.38 (respectively,> dd and mt, J = 15.5 and 9, each of H, -CH ₂ - 14); 2.25 (mt, H: _--CH2 - at position 19); 2.39 (s, 3H, -COCH _3); 2.90 (mt, IH: -C5 H9)

♦ Φ * *

φ φ (-CH <ν 1)]; 3.26 (mt, 1H: --OH at position 2 '); 4.03 and 4.31 (2 d, J = 9, 1H _{each: --CH2} - at position 20); 4.11 (d, J = 7.5, 1H: --H at position 3); 4.62 (mt, 1H: --H at position 2 '); 4.74 (d, J = 4.5, 1H: --H at position 5); 5.28 (broad d, J = 10, 1H: --H at position 3 '); 5.35 (d, J = 10, 1H: - CONH--); 5.68 (d, J = 7.5, 1H: --H at position 2); 6.27 (broad t, J = 9, 1H: --H at position 13); 6.32 (s, 1H: --H at position 10); cd 7.25 to 7.45 (mt, 5H: --CH3 at position 3 &apos;); 7.51 [(t, J = 7.5, 2H: -OCOC ₆ H ₅ (-H at 3 and H at 5)); 7.60 [(t, J = 7.5, 1H: -OCOC ₆ H) ₅ (H at position 4)]; 8.15 (d, J = 7.5, 2H: -000¾ '(-H at position 2 and H at position 6)].

Example 4

The procedure is as in Example 1, but starting from 270 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19- nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate; cyclopropanecarboxylic acid to give 11 mg (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-10beta-cyclopropylcarbonyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor 11-Taxen-13-alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure is as in Example 1, but starting from 110 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-10beta-cyclopropylcarbonyloxy-5beta, 20-epoxy-1-beta-hydroxybeta-8beta-methylene- 9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate to give 62 g of (2R, 3S) - 4alpha-acetoxy2alpha-benzoyloxy-10beta-cyclopropylcarbonyloxy-5beta, 20-epoxy1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen13alpha-γ-3-tert-butoxycarbonylamino-2-hydroxy-3- phenylpropiomate in the form of a white, brittle product having the following characteristics:

♦ 0 · 0 00 00 ···· * 0 0 · 0000 00 0 * 00 0 0 0 0 0 0 * 0 0 0 · 00 0 0 0 0 00 00 000 «0 ·· 000 000 0 0 <0 0

- 30 optical rotation: [alpha] D = -35 (c = 0.5, methanol), @ 1 H-nuclear magnetic resonance spectrum:

(400 MHz, chemical delta shifts in ppm, coupling constants in Hz)

-C 3 H 5 (-CH ₂ - at 2 and -CH ₂ - at 3); 1.27 (s, 3H: --CH3 at position 16 or at position 17); 1.30 (s, 12H: _--CH3 at lórebo at position 17 and --C (CH3) _3); 1.38 (mt, 1H: --H at position 7); 1.67 and 2.26 (respectively dd and nt,

J = 6.5 and 5, 1H _{each: --CH2} -. 19); 1.74 (mt, 1H: -C ₃ H ₅ (CH <in 1); 1.86 (s,

4H: --OH via -CH _3); 2.12 and 2.44 (respectively: d br. D and dt, J = 16 and J = 16 and 4.5, 1H each.: _--CH2 - in 6); 2.25 and 2.38 (respectively: dd and mt, J = 16 at 9,

1H slurry #; -CH ₂ - (14); 2.38 (s, 3H, -COCH _3); 3.27 (mt, 1H: --OH at position 2 '); 4.03 ^and 4.32 (2 d, J = 9, 1H each: _--CH2 - at position 20); 4.10 (d, J = 7.5, 1H: --H at position 3); 4.62 (mt, 1H: --H at position 2 '); 4.72 (d, J = 4.5, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: --H at position 3 '); 5.36 (d, J = 10, 1H: - CONH-); 5.67 (d, J = 7.5, 1H: --H at position 2); 6.28 (broad t, J =

9, 1H: --H at position; 13) ; 6.34 (s, 1H: --H at position 10); cd 7.25 <±> 7.45 (mt, 5H: 3 ' _at 3');

7.51 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3 and H at position 5)]; 7.61 [(t, J = 7.5, 1H: _{--OCOC6 H5} (--H at position 4)]; 8.15 [(d, J = 7.5, 2H: _{--OCOC6 H5} (--H at. 2 and H at position 6)].

Example 5

The procedure is as in Example 1, but starting from 280 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8betamethylene-9-oxo. -19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 415 mg of 2-furancarboxylic acid to give 201 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta- (2-furylcarbonyl) oxy-1beta-hydroxy-7beta, 8beta-methylene 9-oxo-19-nor-11- Taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

0 0 * · * 000000 ·· »♦ 0 0 ♦» 0 0 0 0 0 0 0 0 0 0 0 * * * * * 0 0 · «00« «· · · 0 · 0 0 * · * ·· 000 · * «0 0

The procedure was as in Example 1, but starting from 197 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-10beta- (2-furylcarbonyl) oxy-1-beta-hydroxy-7beta, 8-beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine 5-carboxylate to give 137 mg ( 2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-10beta- (2-furylcarbonyl) oxybeta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen13alpha-yl-3- t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 = -19 (c = 0.5, methanol) .delta.-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ^, delta chemical shifts in ppm, coupling constants in Hz)

1.28 (s, 9H: --C (CH3) _3); 1.32 (s, 3H: _--CH3 at position 16 to 17); 1.38 (s, 3H: _--CH3 at position 16 or vl7); 1.43 (mt, 1H: --H at position 7); 1,70 a

2.28 (respectively; dd and _mt , j = 7 and 5, jh: --CH2 - at position 19); 1.89 (s, 1 H:

-OH in 1); 1.91 (s, 3H: _-CH3); 2.12 and 2.49 (respectively broad d, J = 16 and J = 16 ^and 4.5, 1H inches _: --CH2 - ^{at position} 6); 2.27 and 2.40 (respectively; dd and mt, J = 16)

9, 1H kažlz: _--CH2 - at position 14); 2.40 (s, 3H, -COCH _3); 3.26 (mt, 1H; --OH at position 2 ');

4.05 and 4.33 (2 d, J = 9, 1H-ZDY _{-CH 2} - 20); 4.10 (d, J = 7.5, 1H: --H3); 4.63 (mt, 1H: --H at position 2 '); 4.72 (d, J = 4.5, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: --H at position 3 '); 5.36 (d, J = 10, 1H: - CONH-); 5.71 (d, J = 7.5, 1H: --H at position 2); 6.29 (broad t J =

9, 1H; -H at 13); 6.53 (s, 1H: --H at position 10); 6.56 [(dd, J = 5 and 1.5, 1H: -C ₄ H ₃ O (--H at position 4)]; 7.26 [(d, J = 4, 1H, -C ₄ H ₃ O (--H at position 3)]; from 7.25 to <± 57.45 (mt, 5H: -C ^ 3 '); 7.51 (t, J = 7.5, 2H: _{--OCOC6 H5} ( --H at position 3 and H at position 5)]; 7.61 (t, J = 7.5, 1H: _{--OCOC6 H5} (--H at position 4)]; 7.64 (broad s., 1H, -C ₄ H ₃ O (--H at position 5)]; 8.15 (d, J = 7.5, 2H: _{--OCOC6 H5} (--H 2 and H 6)].

Example 6

The procedure is as in Example 1, except that 44 44 4444 is fefe * fe fe * 4 · 4 «fefe 44 fefe fe .

···· Starting from 280 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy1 beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxene -13alpha-γ-3-tert-butoxycarbonyl-4- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 45mg benzoic acid to give 190mg of (2R, 4S, 5R) 4alpha-acetoxy -2alpha, 10beta-dibenzoyloxy-5beta, 20-epoxybeta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4 phenyl 1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure is as in Example 1, but starting from 190 mg of (2R, 4S, 5R) -4alpha-acetoxy-2a, 10-betadibenzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo. 19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate to give 120 mg of (2R, 3S-4alpha-acetoxy) 2alpha, 10beta-dibenzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-.beta.-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 -28 (c = 0.5, methanol), @ ¹ H-NMR:

(400MHz, CDClg, delta chemical shifts in ppm, coupling constants in Hz)

1.29 (s, 9H: --C (CH3) _3); 1.34 (s, 3H: _--CH3 at position 16 NAX>^H7); 1.42 (s, 3H: _--CH3 at lónáoo at position 17); 1.42 (mt, 1H: --H at position 7); 1,69 a

2.27 (respectively dd and mt, J = 7 and 5, 1H each: --CH2 - at position 19); 1.91 (s, 1H).

-OH in 1); 1.92 (s, 3H: _-CH3); 2.13 and 2.50 (respectively d broad and dt, J = 16 a

J = 16 and 4.5, 1H each _: --CH2 - at 6); 2.26 and 2.41 (respectively dd and mt, J = 16, ag, 1H each _: --CH2 - ^{at position} 14); 2.41 (s, 3H, -COCH _3); 3.26 (mt, 1H: --OH at position 2j;

4.07 and 4.34 (2 d, J = 9, 1H each _: --CH2 - ^{at 2} DEG)! ⁴ - ¹⁸ W - ^J = ⁷ > ⁵ · ^1H: Ή ⁱⁿ 3)!

4.63 (mt, 1H: --H at position 2; 4.75 (d, J = 4.5, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: -);

-H ^at 3 '); 5.37 (d, J = 10, 1H: - CONH-); 5.73 (d, J = 7.5, 1H: --H at position 2); 6.29 (broad t, J = 9.1H: --H at position 13); 6.60 (s, 1H: --H at position 10); from 7.255 to 7.45 (mt, 5H: --C5 H5)

• · flfl flfl flflflfl ♦ * · ··· · flfl fl flfl * • · ··· · fl flfl flflflfl • flflfl flfl flflfl flflfl flfl fl flfl 3 '); 7.49 and 7.51 [(2 t, J = 7.5, 2H - each: _{--OCOC6 H5} (--H at position 3 and H at. 5)]; from 7.55 <337.65 [( mt, 2H: _{--OCOC6 H5} (--H at position 4)]; 8.09 et 8.17 [(2 d, J = 7.5, 2H each:

-OCOC ₆ H ₅ (-H at 2 H at 6)].

Example 7

The procedure is as in Example 1, but starting from 300 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1 beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8betamethylene-9- oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 0.686 cm ³ of 3-methyl anhydride -2-propene to give 237 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy5beta, 20-epoxy-1beta-hydroxy-10beta- (3-methyl-2-propenoyl) oxy-7beta, 8-beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure was as in Example 1, but starting from 270 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyl-5beta, 20-epoxy-1beta-hydroxy-10beta- (3-methyl-2- propenoyl) oxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 192 mg of (2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-10beta- (3-methyl-2-propenoyl) oxy-7beta, 8beta-methylene-9-oxo-19 are obtained. -nor11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate as a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 = -34 (c = 0.5, methanol), .delta.-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ^, delta chemical shifts in ppm, coupling constants in Hz)

1.27 (s, 12H, -C (CH3) ₃ and --CH3 at last year's, and 17);

** ···· * * * 99

4 4 *

4 4 4 4 4 4

1.30 (s, 3H: - (¾ at 16 rrto at 17); 1.39 (mt, 1H: --H at position 7); 1.67 _and 2.26 (respectively dd and mt, J = 6.5) and 5.5 IHkaždý: _--CH2 at position 19); 1.86 (s, 4H: --OH at position 1 and _--CH3); 1.93 (dd, J = 7.5 and 1.5, 3H: _--CH3); 2.11 and 2.47 (respectively. broad d. and dt, J = 16 and J = 16 and 4.5, H each: _--CH2 - in 6); 2.23 _and 2, 39 (respectively, dd and mt, J = 16 and 9, each IH.: _--CH2 - at position 14); 2.38 (s, 3H, -COCH _3); 3.25 (mt, H: OH at 2 '); 4.04 and 4.30 (2 d, J = 9, IH teždý.: _--CH2 - at position 20); 4.12 (d, J = 7.5, H: --H at position 3) 4.62 (mt, 1H: --H at position 2; 4.73 (d, J = 4.5, 1H: --H at position 5)) _: 5.29 (broad d, J = 10, 1H: --H); 3 '); 5.36 (d, J = 10, 1H: - CONH--); 5.68 (d, J = 7.5, 1H: --H at position 2); 5.98 [(dd, J = 16 and 1.5, H: --OCOCH = CH-CH _3)]; 6.27 (broad t., J = 9, H: --H at position 13); 6.40 (s, H: -H at position 10); 7.07 [(dt, J = 16 _and 7.5, H: --OCOCH = CH-CH _3)]; from 7.25 dc7,50 (mt, 5H: -0¾ 3 '); 7.51 [(t, J = 7.5, 2H: ₆ -0C0C _H5 (--H · 3 and H at position 5)]; 7.61 [(t, J = 7.5, IH: -0C0C ₆ H ₅ (-H _{at position} 4)]; 8.15 [(d, J = 7.5, 2H: _{--OCOC6 H5} (--H 2 and H v. 6)].

Example 8

The procedure is as in Example 1, but starting from 220 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9-oxo-19- nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 28 mg of chloroacetic acid to give 100 mg of (2R, 4S, 5R) 4alpha-acetoxy-2alpha-benzoyloxy-10beta-chloroacetoxy5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure was as in Example 1, but starting from 155 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-10beta-chloroacetoxy-5beta, 20-epoxy-1beta-hydroxy-9-oxo-19-nor -11-Taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate

9 9

99

9 9

9 9 • 9 9

9 9

998 99 · * ····

9 9

9 9

998 9 • ·

9 to give 64 mg of (2R, 3S) -4alpha-acetoxy-2alpha-benzoyloxy10beta-chloroacetoxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8-betamethylene-9-oxo-19-nor-11-taxene-13alpha. yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white foam having the following characteristics: optical rotation: / alpha / ₂₀ ~ "39 (c = 0.5, methanol) ¹ H-NMR magnetic resonance spectrum:

(400 MHz, CDCl ^, delta chemical shifts in ppm, coupling constants in Hz)

1.27 (s, 3H: _--CH3 at lómro at position 17); 1.29 (s, 12H: _--CH3 at lónetov 17 -C _{(CH3) 3);} 1.39 (mt, 1H: --H at position 7); 1.71 and 2.26 (respectively: mt A- dd, J = 7 and 5.5, 1H _{each; --CH2} -. 19); 1.87 (s, 4H: --OH at position 1 -CH _3); 2.12 and 2.47 (respectively broad d. Dt, J = 16 and J = 16 and 4.5, 1H each: _--CH2 - ⁱⁿ 6); 2.27 and 2.38 (respectively: dd and mt, J = 16 and 9, 1H each)

-CH ₂ - at 14); 2.40 (s, 3H, -COCH _3); 3.27 (mt, 1H: --OH at position 2j; 4.03 and 4.32 (2 d,

J 9 ^ _lHkaž: _CH ₂ - 20); 4.07 (d, J = 7.5, 1H: --H at position 3); 4.26 (AB limit.,

J = 16, 2H: --OCOCH2 ₍ C1); 4.62 (mt, 1H: --H at position 2 '); 4.74 (d, J = 4.5, 1H: --H at position 5);

5.28 (broad d, J = 10 Hz, 1H: --H at position 3; 5.35 (d, J = 10, 1H: - CONH--); 5.68 (d, J = -);

7.5, 1H: --H2); 6.28 (broad t, J = 9 Hz, 1H: --H at position 13); 6.38 (s, 1H: --H at position 10); cd 7,25do7,45 (mt, 5H: -C ^ j St. 3; 7.51 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position. 3 and H at position 5)] 7.61 [(t, J = 7.5, 1H: _{--OCOC6 H5} (--H at position 4)]; 8.16 (d, J = 7.5, 2H: _{--OCOC6 H5} (- H at 2 and H at 6)].

Example 9

The procedure is as in Example 7, but starting from 300 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1 beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8betamethylene-9- oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 52.4 mg of ethoxycarbonylacetic acid to give with 180 mg φφ · φφφφ φ

(2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta-ethoxycarbonylacetoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

proceeding as in Example 7, but starting from 190 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-10beta-ethoxycarbonylacetoxy-1-hydroxy-7beta, 8beta-methylene -9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine 5-carboxylate to give 73 mg (2R, 3S) ) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-10beta-ethoxycarbonylacetoxy1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen13alpha-yl-3-tert-butoxycarbonylamino-2-hydroxy- 3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] ^D @ 20 = -28 (c = 0.5, methanol), @ ¹ H-NMR:

(300 MHz, CDCl _g ,.; Chemical shifts delta in ppm, coupling constants in Hz)

1.24 (s, 3H: _--CH3 at lónebo at position 17); 1.28 (s, 12H: --C (CH3) ₃ and _--CH3 at position 16 or Yl?); 1.32 (t, J = 7.5, 3H: -OCOCH2COOCH2CH _3); 1.41 (mt, 1H: --H at position 7); 1.72 and 2.22 (respectively, mt DDA, J = 6.5 and 5, 1H each #: _--CH2 - at position 19); 1.89 (s, 4H: --OH at position 1 and _--CH3); 2.15 and 2.50 (respectively broad d · dt, J = 16 and J = 16 and 4.5, _{1H: --CH2} - in 6); 2.28 and 2.40 (respectively dd and mt, J = 16 and 9, 1H each # -CH ₂ - ^14); 2.42 (s, 3H, -COCH _3); 3.32 (mt, 1H: --OH at position 2 '); 3.58 (AB limit, 2H):

-OCOCH ₂ COOCH ₂ CH ₃ ); 4.08 and 4.35 (2 d, J = 9 Hz, 1H each #: _--CH2 - at position 20); 4.10 (d, J = 7.5, 1H: --H at position 3); 4.28 (q, J = 7.5, 2H: -OCOCH ₂ COOCH ₂ CH _3); 4.63 (mt, 1H; --H at position 2; 4.75 (d, J = 4.5, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: --H at position 5); 3 '); 5.39 (d, J = 10, 1H: - CONH--); 5.69 (d, J = 7.5, 1H: --H at position 2); 6.30 (broad t, J); = 9, 1H: --H at position 13) 6.38 (s, 1H: --H at position 10) - from 7.25037.50 (mt, 5H: --C1 H5);

- 37 v ♦ ♦ v v 3 3 3 3 3 3 3j; 7.53 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3 and H at position 5)]; 7.62 [(t, J = 7.5, IH: _{--OCOC6 H5} (--H. 4)]; 8.18 [(d, J = 7.5, 2H: _{--OCOC6 H5} (--H 2 and H 6)].

Example 10

The procedure was as in Example 1, but starting from 300 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1 beta, 10beta-5beta, 20-epoxy-7beta, 8beta-methylene-9. -oxo19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 584 mg acrylic anhydride to give 160 mg (2R, 4S, 5R) -4alpha-acetoxy-10beta-acryloyloxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen13alpha-yl-3 tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure was as in Example 1, but starting from 196 mg of (2R, 4S, 5R) -4alpha-acetoxy-10betaacryloyloxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy7beta, 8beta-methylene-9-oxo. -19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate to give 113mg of (2R, 3S) -4alpha-acetoxy -1Betaacryloyloxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 = -39 (c = 0.5, methanol) .delta.-nuclear magnetic resonance spectrum:

(400 MHz, CDClg, delta chemical shifts in ppm, coupling constants in Hz)

1.27 [s, 12H: --C (CH3) ₃ and CH _3. 16nero at 17];

1.30 (s, 3H: _--CH3 at position 16 rebov 17); 1.39 (mt, 1H: --H at position 7); 1.68 and 2.26 (respectively dd amt, J = 6.5 and 5, 1H each: --CH2 - ^{at position} 19); 1.86 (s, 1H: --OH 1); 1.88 (s, 3H: _-CH3); 2.13 a; 2.49 (respectively d or in dt, J = 15 and J = 15

and 4 lHkaždý: _--CH2 - in 6); 2.25 and 2.39 (2 mts, _{lHkažáý: --CH2} - at position 14); 2.38 (s, 3H: --COCH3); 3.27 (mt, 1H: --OH at position 2 '); 4.06 and 4.34 (2 d, J = 9 ^ lHkaž: _--CH2 - at position 20); 4.13 (d, J = 7.1H: --H at position 3) _; 4? 3 (mt, 1H: --H at position 2 '); 4.75 (d, J = 4, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: --H at position 3 '); 5.35 (d, J = 10, 1H: - CONH--); 5.69 (d, J = 7, 1H: --H at position 2); 5.95 et 6.53 (2 dd, respectively, J = 10 and 1.5 and J = 16 and 1.5, 1H Kazaa: --OCOCH = CH _2); 6.27 (dd, J = 16 and 10, 1H: --OCOCH = CH _2); 6.29 (mt, 1H: --H at position 13); 6.42 (s, 1H: --H at position 10); * from 7.25 to 7.45 (mt, 5H: -C ₆ H _5, 3j; 7.53 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3 and H at. 5)]; 7.63 [(t, J = 7.5, 1H: _{--OCOC6 H5} (--H at position 4)]; 8.17 (d, J = 7.5, 2H: _--OCOC6 H ₅ (-H at 2 and H- at 6)].

Example 11

The procedure is as in Example 1, but starting from 250 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1 beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9. oxo19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 41 mg of 3-pyridinecarboxylic acid to give with 269 mg of (2R, 4S, 5R) -4alpha-acetoxy 2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-10beta- (3-pyridylcarbonyl) oxy-19-nor 11-Taxen-13-alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure was as in Example 1, but starting from 264 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo. 1Beta- (3-pyridylcarbonyl) oxy-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate afforded 169 mg (2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8betamethylene-9-oxo-10beta- (3-pyridylcarbonyl) oxy-19-nor-11-taxen13alpha-yl -3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product, which has the following properties: &lt; tb &gt; ______________________________________ &lt; tb &gt; ·· ♦ · ·· ··

optical rotation: [.alpha.] D @ 20 = -25 (c = 0.5, methanol), .delta.-nuclear magnetic resonance spectrum:

(400 MHz, CDCl ^, delta chemical shifts in ppm, coupling constants in Hz)

1.29 [(s, 9H: --C _{(CH3) 3];} 1.34 (s, 3H: _--CH3 at 16n at a = 17); 1.41 (s, 3H: _--CH3 at. 1.65 (mt, 1H: --H at position 7), 1.74 a

2.29 (respectively dd and mt, J = 6.5 and 5.5, 1H each; --CH2 - at position 19); 1.94 (s,

3H: _--CH3); 2.14 and 2.52 (respective broad and dt, J = 16 in J = 16 and 4, 1H each: --CH2 - at position 6); 2.29 and 2.43 (2 mts, 1H each: --CH2 - at position 14); 2.43 (s, 3H, -COCH _3); 3.31 (mt, 1H, --OH at 2j .: 4.07, 4.35 (2 d, J = 9, 1H each.: _--CH2 - at position 20); 4.17 (d, J = 7, 4.74 (mt, 1H: --H at position 2; 4.77 (d, J = 4, 1H: --H at position 5); 5.30 (broad d, 1H: --H at position 3); J = 10, 1H: --H at position 3; 5.37 (d, J = 10, 1H: - CONH--); 5.74 (d,

J = 7.5, 1H: --H at position 2); 6.32 (broad t, J = 8.5, 1H: --H at position 13) _: 6.63 (s, 1H: --H at position 10); from 7,25do7,45 (mt, 5H, -C ₆ H _5, 3j; 7.45 [(dd, J = 8 and 5.5, 1H: H ₅ -OCOC ₄ N (--H at position 5)]; 7.53 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position. 3 and H at position 5)]; 7.63 [(t, J = 7.5, 1H:

_{--OCOC6 H5} (--H at position 4)]; 8.18 [(d, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 2a -Hv 6)]; 8.36 [(dt, J = 8 and 1.5, 1H: -OCOC ₅ H ₄ N (--H at position 4)]; 8.84 (dd, J = 5.5 and 1.5, 1H: H ₅ -OCOC _4N (-Hv 6)]; 9.29 (d, J = 1.5,1H: -OCOC ₅ H ₄ N (--H _{at position} 2)].

Example 12

The procedure was as in Example 1, but starting from 250 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8betamethylene-9-oxo. -19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 42 mg of 3-thiophenecarboxylic acid to give 180 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta-hydroxy-7beta, 8beta-methylene-9-oxo-10beta- (3thenoyl) oxy-19-nor-11-taxene -13alpha-yl-3-tert-butoxycarbonyl · »

4 4444 • 4

4 4 4 4

2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The procedure is as in Example 1, but starting from 175 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-10beta. - (3-thenoyl) oxy-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine 5-carboxylate to give 102 mg ( 2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8betamethylene-9-oxo-10beta- (3-thenoyl) oxy-19-nor-11-taxen-13alpha-yl-3- t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 ⁼ ~ 16 (c = 0.5, methanol) @ 1 H-NMR:

(400 NHz, CDCl3, delta chemical shifts in ppm, coupling constants J in Hz)

1.30 [s, 9H: --C (CH3) _3]; 1.33 (s, 3H: _--CH3 at position 16 nan vl7); 1.40 (s, 3H: _--CH3 at. 16 or 7-yl); 1.44 (mt, 1H: --H at position 7); 1.72 and 2.29 (2 dd, respectively, J = 6.5 and 5.5 and J = 10 and 6.5, 1H each: CH _2-19); 1.92 (s,

4H: _--CH3 and --OH at. _L): 2.14 et 2.51 (respectively broad d. And dt, J = 16 and. J = 16 and 4, 1H _{each: --CH2} - in 6); 2.26 and 2.42 (2 mts, 1H each .; · _--CH2 - at position 14); 2.42 (s, 3H, -COCH _3); 3.27 (mt, 1H: --OH at position 2j; 4.06 and 4.32 (2 d, J = 9, 1H each):

_--CH2 - at position 20); 4.17 (d, J = 7.5, 1H: --H at position 3); 4.63 (mt, 1H: --H at position 2; 4.76 (d, J =

4, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: --H at position 3j; 5.35 (d, J = 10, 1H: - CONH -)); 5.72 (d, J = 7.5, 1H: - 6.30 (broad t, J = 8.5, 1H: --H at position 13);

6.53 (s, 1H: --H at position 10); od7,25 <to7,45 [mt, 6H, C ₆ H _{5 3} * -OCOC ₄ H ₃ S (--H _at position 5)]; 7.53 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3 and H at position 5)]; 7.57 [broad d. J = 5.5,

1H: -OCOC ₄ H ₃ S (-H at position 4)]; 7.62 [(t, J = 7.5, 1H: _{--OCOC6 H5} (--H at position 4)]; 8.17 [(d,

J = 7.5, 2H: -OCOC6H _H5 (--H at position 2 et en H 6)]; 8.19 [mt, 1H: -OCOC ₄ H ₃ S (-H en 2)].

· «Φφφφ

Example 13

The procedure is as in Example 1, but starting from 300 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8betamethylene-9-oxo. -19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 713 mg of vinyl acetic anhydride to give 114 mg (2R, 4S, 5R) -4alpha-acetoxy-10beta-allylcarbonyloxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl -3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate as a white, brittle product.

The vinyl acetic anhydride can be prepared as follows:

To a solution of 3.42 g of N, Ν ' -dicyclohexylcarbodiimide in 20 cm @ 3. dichloromethane, maintained under an argon atmosphere, is added dropwise with stirring at a temperature close to 20 ° C.

2,8 cn? vinylacetic acid. The reaction mixture is kept under stirring at a temperature close to 20 ° C for 3 days and then filtered through a glass frit lined with celite. The glass frit is then washed twice with 10 cm 3 of dichloromethane each, the filtrates are combined and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. 2.96 g of acetic anhydride are thus obtained in the form of a yellow oil.

The procedure is as in Example 1, but starting from 140 mg of (2R, 4S, 5R) -4alpha-acetoxy-10beta-allylcarbonyloxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy7beta, 8beta-methylene-9. oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate to give 80mg of (2R, 3S) -4alpha -acetoxy-10betaallylcarbonyloxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonylamino-2-hydroxy-3 -phenylpropionate in ··· 4 · 4

4 4 444444 • 4 4 4 44 ·· 44 ··

444 444 44 »44 444 44 44 4 form a white brittle product having the following characteristics:

optical rotation: / alpha / ₂ θ ⁼ ”34 (c = 0.5, methanol) ¹ H nuclear magnetic resonance spectrum:

(400 MHz, CDCl 3, chemical delta shifts in ppm, coupling constants J in Hz)

1.26 (s, 3H: --CH3 at position 16 or 17); 1.29 [s, 12H: --C _{(CH3) 3.} -CH ₃ 16 afterwards 17]; 1.38 (mt, 1H: --H at position 7); 1.69 and 2.26 (2 dd, respective- J = 6.5 and 5.5 and J = 10 and 6,5,1H teždý: _--CH2 - at position 19); 1.84 (s, 1H: --OH at position 1); 1.85 (s, 3H: _-CH3); 2.12 and 2.46 (respectively broad d. And dt, J = 16 and J = 16 and 4, 1H each _#: _CH ₂ - in 6); 2.24 2.40 (2 mts, 1Hkaždý: _--CH2 - at position 14); 2.40 (s, 3H, -COCH _3); 3.27 (mt, 3H: --OH at position 2 'and ₂ OCOCH = CH ₂ -CH) / 4.05 and 4.32 (2 d, J = 9, 1H each: _--CH2 -in 20); 4.11 (d, J = 7.5, 1H: --H at position 3); 4.63 (mt, 1H: --H at position 2 '); 4.73 (d, J = 4, 1H: --H at position 5); 5.24 and 5.26 (2 dd, respectively, J = 8 and 2 and J = 18. 2, 1H _each.: OCOCH ₂ CH = CH _2); 5.29 (broad d, J = 10, 1H: --H 3 '); 5.34 (d, J = 10, 1H: - CONH--); 5.69 (d, J = 7.5, 1H: --H at position 2); 6.00 (mt, 1H: -CH ₂ OCOCH = CH _2); 6.28 (broad t, J = 8.5, 1H: --H at position 13); 6.34 (s, 1H: --H at position 10);

CD. 7,25do7,45 (mt, 5H: _{--C6 H5} at position 3 '); 7.53 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3 and H at position _5)]; 7.62 [(t, J = 7.5, 1H: _--OCOC6 H5 (--H at position 4)]; 8.15 (d, J = 7.5, 2H; -OCOC6H _H5 (--H in. 2 and H 6)].

Example 14

The procedure was as in Example 1, but starting from 300 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8beta-methylene-9. oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 45 mg of 3-furancarboxylic acid to give 282 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta- (3-furoyl) oxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxene -13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate

In the form of a white, fragile product.

The procedure was as in Example 1, but starting from 282 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-10beta- (3-furoyl) oxy-1beta-hydroxy7beta, 8-beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate yielded 143 mg (2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta- (3-furoyl) oxy-1-beta-hydroxy-7beta, 8beta-methylene-9-oxo-19-nor-11-taxen-13alpha-yl3 - t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [alpha] ^D20 = -26 (c = 0.5, methanol),

H-nuclear magnetic resonance spectrum:

(400MHz, CDCl ^, delta chemical shifts in ppm, coupling constant J in Hz)

1.29 [mt, 12H: --C (CH3) ₃ and _--CH3 at position 16 or at position 17]; 1.35 (s, 3H: _--CH3 at Loreto 17); 1.43 (mt, 1H: --H at position 7); 1.70 _and 2.27 (2 dd, respectively J = 6.5 and 5.5, J = 10 and 5.5, 1H each: --CH2 - 19); 1.87 (s,

1H: --OH at 1); 1.92 (s, 3H: _-CH3); 2.13 and 2.50 (respectively broad d. And dt, J = 16 and J = 4 and, lHkaž #: _--CH2 -in 6); 2.27 and 2.40 (2 mts, 1H each #: _--CH2 at position 14); 2.40 (s, 3H, -COCH _3); 3.27 (mt, 1H: --OH at position 2 '); 4.05 and 4.33 (2 d, J = 9,

# 1H each: _--CH2 - at position 20); 4.15 (d, J = 7.5, 1H: --H at position 3); 4.63 (mt, 1H: --H _{at position} 2 ');

4.76 (d, J = 4, 1H: --H at position 5); 5.29 (broad d, J = 10, 1H: --H at position 3 '); 5.36 (d, J = 10)

1H: -CONH-); 5.72 (d, J = 7.5, 1H: --H at position 2); 6.30 (broad t, J = 8.5, 1H: --H _{at position} 13); 6.52 (s, 1H: --H at position 10); 6.79 (d, J = 1.5, 1H: --OCOC ₄ H ₃ O (-H en 4)); from 7.25 to 7.45 (mt, 5H; -C ₆ H ₅ en 3j; 48 (broad t., J = 1.5, 1H: H ₃ -OCOC ₄ O (--H at position 5)];

7.53 [(t, J = 7.5, 2H: -OCOC6H _H5 (--H at position 3 and H at position 5)]; 7.63 [(t, J = 7.5, 1H: ₅ -OCOC6H (- H at position 4)] 8.09 [s broad, 1H: -OCOC ₄ H ₃ O (-H at position 2)]; 8.17 [(d, J = 7.5,

2H: _{--OCOC6 H5} (--H at position 2 and H at position 6)].

Example 15 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4

The procedure is as in Example 1, but starting from 300 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-1beta, 10beta-dihydroxy-5beta, 20-epoxy-7beta, 8betamethylene-9-oxo. -19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate and 50 mg of 4-pyridinecarboxylic acid to give 296 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy1beta-hydroxy-7beta, 8beta-methylene-9-oxo-10beta- (4-pyridylcarbonyl) oxy-19-nor-11 -taxen-13alpha-yl-3-tert-butylcarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylates as a white, brittle product.

proceeding as in Example 1, but starting from 296 mg of (2R, 4S, 5R) -4alpha-acetoxy-2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8beta-methylene-9-oxoObeta - (4-pyridylcarbonyl) oxy-19-nor-11-taxen-13alpha-yl-3-tert-butoxycarbonyl-2- (4-methoxyphenyl) -4-phenyl-1,3-oxazolidine-5-carboxylate to give 159 mg (2R, 3S) -4alpha-acetoxy2alpha-benzoyloxy-5beta, 20-epoxy-1beta-hydroxy-7beta, 8betamethylene-9-oxo-10beta- (3-pyridylcarbonyl) oxy-19-nor-11-taxen13alpha-yl-3 - t-butoxycarbonylamino-2-hydroxy-3-phenylpropionate in the form of a white, brittle product having the following characteristics:

optical rotation: [.alpha.] D @ 20 = -23 (c = 0.5, methanol). @ 1 H-NMR spectral:

(300 MHz, CDCl3, delta chemical shifts in ppm, coupling constants J in Hz)

1.27 [(s, 9H: --C _{(CH3) 3];} 1.32 (s, 3H: _--CH3 at position 16 or V L?), 1.39 (s, 3H: _--CH3 at position 16 or 1.72 (mt, 1H: --H at position 7), 1.70 a

2.27 (respectively dd and mt, J = 6 and 5.5, 1H each: --CH2 - at position 19); 1.90 (s, 3H: _-CH3); 1.91 (s, 1H: --OH at position 1); 2.13 and 2.50 (respectively d broad at dt, J = 16 and J = 16 and 4, 1H each; --CH2 - at position 6); 2.27 and 2.40 (2 mts, H each: _--CH2 - at position 14); 2.40 (s, 3H: --COCH3); 3.27 (mt, 1H: --OH at position 2 '); 4.04 and 4.32 (2 d, J = 9, IH each -CH ₂ - 20); 4.13 (d, J = 7.5, 1H: --H _{at position} 3); 4.63 (mt, 1H: --H at position 2 ');

«·· ·

4.76 (d, J = 4, 1H: --H at position 5); 5.27 (broad d, J = 2, 1H: - 3 '); 5.33 (d, J = 10, 1H: - CONH-); 5.72 (d, J = 7.5, 1H: --H at position 2); 6.29 (broad t, J = 8.5, 1H: --H at position 13); 6.58 (s, 1H: --H at position 10); from 7,25čb7,45 (mt, 5H: _{--C6 H5} at position 3 '); 7.53 [(t, J = 7.5, 2H: _{--OCOC6 H5} (--H at position 3 and H at position 5)]; 7.63 [(t, J = 7.5, IH: _--OCOC6 H5 (-H _{at position} 4)]; 7.88 [(dd, J = 6 and 1.5, 2H: -OCOC ₅ H ₄ N (-H at position 3 and -H at position 5)); 8.17 [( d, J = 7.5, 2H: _{--OCOC6 H5} (--H at 2a. H-6)]; 8.82 [(dd, J = 6 et 1.5, 2H: H ₄ -OCOC ₅ N (-H _at 2 and -H at 6)].

The novel compounds of formula (I) wherein Z is a group of formula (II) exhibit significant inhibitory activity against abnormal cell proliferation and have therapeutic properties allowing the treatment of diseases having pathological conditions associated with said abnormal cell proliferation. Such pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs, including, but not limited to, muscle, bone or conjunctive tissues, skin, brain, lung, genital organs, lymphatic or renal system, blood cells or mammary gland cells. liver, gastrointestinal tract, pancreas and thyroid and adrenal glands. These pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangiocarcinoma, choriocarcinoma, neuroblastoma, Wilms' tumor, Hodgkin's disease, melanomas, myeloma multiplex, chronic leukemia, acute or chronic granulocyte lymphomas. New compounds according to the invention

Climbing lesions are particularly useful for the treatment of ovarian cancer. The compounds of the invention may be used to prevent or delay the symptoms or recurrence of pathological conditions or to treat such pathological conditions.

The compounds of the invention may be administered to a patient in a variety of forms suitable for the mode of administration selected, with parenteral administration being the preferred route of administration. Administration by the parenteral route includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. A particularly preferred administration is intraperitoneal or intravenous administration.

The present invention also provides pharmaceutical compositions comprising at least one compound of formula I in a sufficient amount to be used in human or veterinary therapy. These compositions may be prepared by conventional methods using at least one additive, at least one carrier or at least one excipient which is pharmaceutically acceptable. Suitable carriers include diluents, sterile aqueous solutions and various non-toxic solvents. Said compositions preferably take the form of aqueous solutions or suspensions or injectable solutions which may contain emulsifying agents, coloring agents, preservatives and stabilizing agents. However, the compositions may also take the form of tablets, pills, powders or granules for oral administration.

The choice of excipients and excipients will be determined by the solubility and chemical properties of the particular compound, the route of administration and pharmaceutical usage.

For parenteral administration, aqueous or non-aqueous sterile solutions or suspensions are used. Natural vegetable oils such as olive oil, sesame oil or paraffin oil, or injectable organic esters such as ethyl oleate may be used to prepare such non-aqueous solutions or suspensions. The aqueous sterile solutions may be

comprising a solution of a pharmaceutically acceptable salt in water.

Such aqueous solutions are suitable for intravenous administration when their pH has been appropriately adjusted and their isotonicity has been realized, for example with a sufficient amount of sodium chloride or glucose. Sterilization may be performed by heating or by any other means which does not compromise the quality of the pharmaceutical composition.

It goes without saying that all substances forming part of the pharmaceutical compositions of the invention must be pure and non-toxic in the amounts used.

Said compositions may contain at least 0.01% of a therapeutically active compound. The amount of active ingredient in the pharmaceutical composition is such that a suitable dosage can be prescribed. Preferably, the pharmaceutical compositions are prepared in such a manner that the unit dose contains 0.01 to 1000 mg of the effective dose for parenteral administration.

Treatment may be performed concurrently with other therapeutic procedures, including administration of antineoplastic drugs, monoclonal antibodies, immunological or radiotherapeutic procedures, or administration of biological response modifiers. Such biological response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons (alpha, beta, or delta) and the TNF agent. Other chemotherapeutic agents suitable for treating disorders caused by abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorabucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomustine, semustine and streptozocin, triazines dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluoruracil and cytarabine, purine analogs such as mercaptopurine and thioguanine, natural substances such as vinca alkaloids such as vinblastine, vincristine and vendesin, epipodophylloside, epipodophyllotoxide anti48

biotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents such as platinum coordination complexes such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazine derivatives such as procarbortic acid, adrenals such as procarbazine, adrenes such as procarbortin, and aminogluethymid, hormones and antagonists such as adrenocorticosteroids such as prednisone, progestins such as hydroxyprogesterone caproate, methoxyprogesterone acetate and megestrol acetate, oestrogens such as diethylstilbestrol, antioestrogens such as tamoxifen, androgens such as testosterone propionate.

The dosages used in the methods of the invention are those that allow for prophylactic treatment or guarantee maximum therapeutic response. These doses vary according to the route of administration, the particular active compound selected, and finally the characteristics of the patient being treated. In general, such doses are those that are therapeutically effective for treating disorders caused by abnormal cell proliferation. The compounds of the invention may be administered as often as necessary to achieve the desired therapeutic effect. Some patients may show a rapid response at relatively high or low doses and need either low or no maintenance dose. Generally, low doses are used at the beginning of treatment and then, if necessary, increasing doses are administered until optimal effect is achieved. In other patients, it may be necessary to administer maintenance doses one to eight times a day, preferably one to four times a day, depending on the physiological needs of the subject being considered. It is also possible that in some patients it will be necessary to give only two daily administrations.

In humans, said doses are generally 0.01 to 200 mg / kg. For intraperitoneal administration, doses will generally be 0.1 to 100 mg / kg and preferably 0.5 to 50 mg / kg, especially 1 to 10 mg / kg. For intravenous administration said doses are generally 0.1 and 50 mg / kg, preferably 0.1 to 5 mg / kg, in particular 1 to 2 mg / kg. It is self-evident that the choice of the most aqueous dose will be influenced by the route of administration chosen, the patient's weight and general health as well as the age and age of the patient. all other factors that could affect the effectiveness of the treatment.

The following is an example of a pharmaceutical composition of the invention.

mg of the compound obtained in Example 1 is dissolved in 1 cm @ ³ of Emulphor EL 620 and 1 cm @ ^{3 of} ethanol and then diluted with 18 cm @ ^{3 of} physiological serum. The obtained pharmaceutical composition according to the invention is administered during a one-hour infusion by introduction into saline.

ING. EDUARD HAKR patent attorney

Claims (13)

(X) wherein R 1, R 2 are as defined in any one of claims 1, 2 or 3, R 8 and R 4 are as defined in claim 4, or a derivative thereof such as a halide, symmetric anhydride or mixed anhydride, whereupon the protecting groups R? or R 8 and R 6 hydrogen atoms. PATENT CLAIMS 1) when Rg represents a hydrogen atom and R _? means a hydroxy-protecting group, then these protecting groups are replaced by hydrogen atoms using a mineral or organic acid, used alone or in a mixture, working in an organic solvent selected from alcohols, ethers, esters, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and nitriles, at a temperature between -10 and 60 ° C, CLAIMS 1. Taxoids of the general formula I in which R is a straight or branched alkyl group having 1 to 8 carbon atoms, substituted with a substituent selected from the group consisting of halogen atoms of fluorine, chlorine, bromine and iodine, amino, alkylamino in which the alkyl radical contains 1 to 4 carbon atoms, dialkylamino a group in which the alkyl radicals contain 1 to 4 carbon atoms or, together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocyclic group optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen atoms and is optionally substituted with C 1 -C 4 alkyl or phenyl or phenylalkyl, the alkyl radical of which contains 1 to 4 carbon atoms, carboxy, alkyloxycarbonyl, the alkyl radical of which contains 1 to 4 carbon atoms, cyano, carbamoyl , N-alkylcarbamoyl 2) when R 8 and R 6 form an oxazolidine ring of formula VI R _r N ^ O (knows) R ₈ R ₉ • 9 · 9 9 58 58 · 99 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl or 3-thienyl. The taxoids of claim 1, wherein: Z is hydrogen or a group of formula II wherein R represents a benzoyl radical or a radical _R2-O-CO- in which _R2 represents a tertbutyl radical and R represents an alkyl group having 1 to 6 coal- 55 φ φ φ · · · φ φ φ φ φ φ φ φ φ φ * * * * * φ φ φ φ φ φ φ φ φ φ k k k k k Phenyl, optionally substituted with one or more identical or different substituents selected from the group consisting of halogen atoms (fluorine atom, chlorine atom), alkyl group (methyl group, alkoxy group (methoxy group), dialkylamino group (dimethylamino group) ), acylamino (acetylamino), alkoxycarbonylamino (t-butoxycarbonylamino) and trifluoromethyl, or 2-furyl, 3-furyl a group, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl and R represents a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group, 3 has the above meaning, which is acylated with benzoyl chloride. wherein the phenyl core is optionally substituted with thenoyl chloride, furoyl chloride or a compound of formula VIII R ₂ -O-CO-X (VIII) wherein R ₂ is as defined above and X represents a halogen atom or a -O-R ₂ or -O-CO-OR ₂ radical to form a compound of formula (I), wherein: wherein Z represents a group of formula II, b) when R 1 is an optionally substituted benzoyl, thenoyl or furoyl group or R ₂ O-CO-, in which R ₂ is as defined above, R 8 is a hydrogen atom or a C 1 -C 4 alkoxy group atoms or a phenyl group substituted by one or more alkoxy groups having from 1 to 4 carbon atoms and R 8 represents a hydrogen atom, then replacing the protecting group formed by R 8 and R 8; The hydrogen atoms are carried out in the presence of a mineral or organic acid, used alone or in a mixture, in a stoichiometric or catalytic amount, working in an organic solvent at a temperature between -10 and 60 ° C. Third taxoid according to claim 1 of formula I wherein Z represents a hydrogen atom or a group of formula II wherein R represents a benzoyl radical or a radical of the formula Rg-O-CO- in which _R2 represents a tertbutyl radical and R 8 is isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, Process for the preparation of a compound according to any one of claims 1, 2 or 3, characterized in that the compound of formula III is esterified. 99 9999 »· 9 9 4-thiazolyl or 5-thiazolyl; and R is cyclopropyl, cyclopentyl, phenyl, 2-pyridyl, 2-thienyl or 2-furyl. A 4- to 6-membered saturated heterocyclic group which is optionally substituted by one or more alkyl groups having 1 to 4 carbon atoms / represents a straight or branched alkyl group having 1 to 8 carbon atoms, a straight or branched alkenyl group having 2 to 8 carbon atoms straight or branched (C 2 -C 8) alkynyl, (C 3 -C 6) cycloalkyl, phenyl or alpha or beta-naphthyl optionally substituted by one or more substituents selected from halogen, alkyl group, alkenyl, alkynyl, φφφφ Ry φ a a ry a a a a ry a ry ry ry ry ry ry aryl, aralkyl, alkoxy, alkyl, thio-alkyl, alkylthio-alkyl hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amio, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, a nitro group, a nitro group, a trifluoromethyl group, or a 5-membered aromatic heterocyclic group containing one or more of the same or different heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with one or more of the same or different substituents selected from halogen, alkyl sk upine, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkoxycarbonyl, alkoxy, aryloxy and acylamino, wherein in the substituents phenyl or alpha or beta-naphthyl and aromatic heterocyclic groups the alkyl and alkyl radicals of the other groups contain 1 to 4 carbon atoms and the alkenyl and alkynyl groups contain 2 to 8 carbon atoms and aryl groups are phenyl or alpha or beta-naphthyl groups. A group in which the alkyl radical contains from 1 to 4 carbon atoms, the N, N-dialkylcarbamoyl group in which the alkyl radicals contain from 1 to 4 carbon atoms or form with a nitrogen atom, to which they are bound, a saturated 5- or 6-membered heterocyclic group which optionally contains a second heteroatom selected from oxygen, sulfur and nitrogen atoms and is optionally substituted by an alkyl group having 1 to 4 carbon atoms or a phenyl group or a phenylalkyl group whose alkyl the remainder contains 1 to 4 carbon atoms, straight or branched chain C 2 -C 8 alkenyl, straight or branched C 2 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, said groups they may be optionally substituted with a substituent selected from the group consisting of halogen atoms of fluorine, chlorine, bromine and iodine, amino, alkylamino in which the alkyl radical contains 1 to 4 carbon atoms, dialkylamino in which the alkyl radicals contain 1 to 4 carbon atoms Or, together with the nitrogen atom to which they are attached, form a saturated 5- or 6-membered heterocyclic group optionally containing a second heteroatom selected from oxygen, sulfur or nitrogen atoms and optionally substituted with an alkyl group containing 1 carbon atom; up to 4 carbon atoms or a phenyl or phenylalkyl group having an alkyl radical of 1 to 4 carbon atoms, a carboxy group, an alkyloxycarbonyl group having an alkyl radical of 1 to 4 carbon atoms, a cyano group, a carbamoyl group, an N-alkylcarbamoyl group whose alkyl group the radical contains from 1 to 4 carbon atoms, the N, N-dialkylcarbamoyl group in which the alkyl radicals contain from 1 to 4 carbon atoms or form, with the nitrogen atom to which they are attached, a saturated 5- or 6-membered heterocyclic group, which optionally contains a second heteroatom selected from oxygen, sulfur and nitrogen atoms and is optionally substituted with C 1 -C 4 alkyl or phenyl or phenylalkyl having an C 1 -C 4 alkyl radical, or - a phenyl group or a 5- or 6-membered heterocyclic aromatic group containing as the heteroatom an oxygen atom, a sulfur atom or a nitrogen atom, and represents a hydrogen atom or a group of the general formula II OH in which it represents a benzoyl group, which is optionally substituted. bolded with one or more identical or different substituents selected from the group consisting of halogen atoms, (C1-C4) -alkyl, (C1-C4) -alkoxy and trifluoromethyl, thenoyl or furoyl, or T T-O -CO-, in which R ₂ represents C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 7 -cycloalkyl group optionally substituted with one or more substituents selected from the group consisting of halogen atoms, hydroxy, C 1 -C 4 alkoxy, dialkylamino, wherein each alkyl radical contains 1 to 4 carbon atoms It is a atom, a piperidino group, a morpholino group, a 1-piperazinyl group, which is optionally substituted in the 4-position by an alkyl group containing 1 to 4 carbon atoms or a phenylalkyl group in which the alkyl moiety ob C 1 -C 4 -cycloalkyl, C 3 -C 6 -cycloalkyl, C 4 -C 6 -cycloalkenyl, phenyl optionally substituted by one or more substituents selected from the group consisting of halogen atoms, C 1 -C 4 alkyl 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms, a cyano group, a carboxyl group and an alkoxycarbonyl group in which the alkyl radical contains 1 to 4 carbon atoms, - a phenyl or alpha- or beta-naphthyl group optionally substituted by one or more substituents selected from the group consisting of halogen atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, 4 4 4 4 4 4 * Process according to Claim 4, characterized in that the esterification is carried out using an acid of the formula IV in the presence of a condensing agent and an activating agent. The reagents in an organic solvent at a temperature between -10 and 90 ° C are used. A 5-membered aromatic heterocyclic group, preferably selected from the group consisting of furyl and thienyl, or Process according to Claim 4, characterized in that the esterification is carried out using an acid of the formula IV in the form of a symmetrical anhydride, in the presence of an activating agent in an organic solvent and at a temperature between 0 and 90 ° C. Process according to claim 4, characterized in that the esterification is carried out using an acid of the formula IV in the form of a halide or mixed anhydride with an aliphatic or aromatic acid, optionally prepared in situ, in the presence of a base and in an organic solvent at a temperature between 0 and 80 ° C. Method according to claim 4, characterized in that the replacement of the protecting groups and / or R 8 and R 8 by hydrogen atoms is carried out according to the nature of the protecting groups as follows: 9. A process for the preparation of a compound of formula (I) wherein Z is a group of formula (II), characterized by esterifying a baccatin III derivative of formula (XI) using an acid of formula (X) 9 Wherein R 6 and R 8, which are the same or different, are hydrogen or C 1 -C 4 alkyl, aralkyl having 1 to 4 carbon atoms and aryl the radical is a phenyl group optionally substituted by one or more alkoxy groups having 1 to 4 carbon atoms, or an aryl group representing a phenyl group optionally substituted by one or more alkoxy groups having 1 to 4 carbon atoms and either Rg is a alkoxy group having 1 to 4 carbon atoms 4 carbon atoms or a trihalomethyl group or a phenyl group substituted with a trihalomethyl group and Rg represents a hydrogen atom or Rg and Rg together with the carbon atom to which they are attached form a 4- to 7-membered ring, then a protecting group formed by Rg and R-, will replace hydrogen atoms depending on the meanings of Rg and Rg follow The more steps: (a) when R 6 is tert-butoxycarbonyl, R g and R g, which are the same or different, are alkyl or aralkyl or aryl or R g is trihalomethyl or phenyl substituted with trihalomethyl and R _Q y is atom hydrogen or Rg and Rg together form a 4- to 7-membered ring, then the ester of formula V is reacted with a mineral or organic acid, optionally in an organic solvent, to form a compound of formula VII wherein R is 9 9 9 9 9 99 99 999 8 9 9 9 99 999 9 9 9 9 9 9 9 Wherein R 6 and R 8 are as defined in any one of claims 1, 2 or 3 and either R 5 is a hydrogen atom and R 6 is a hydroxy-protecting group or R 8 and R 6 together form a 5 or 6-membered saturated heterocyclic group, using an acid of formula IV R-CO-OH (IV) wherein R is as defined above, or a derivative thereof such as a halide, symmetrical anhydride or mixed anhydride, to give a compound of formula V wherein Rp R8, R8 and R8 are as defined above whereupon R is replaced? or Rg and R? hydrogen atoms. 9 99,999 9 9 99,999,999 9 9 9 9 9 Process according to claim 9, characterized in that the esterification is carried out by a process according to any one of claims 5, 6 or 7. Process according to Claim 9, characterized in that the protecting groups R 6 or R 8 and R 8 are replaced by hydrogen atoms under the conditions set forth in claim 8. A process for the preparation of a compound according to claim 1, wherein Z represents a hydrogen atom, characterized in that the compound of the formula XII in which Z ₁ represents a hydroxy-protecting group is esterified, to Use of an acid of formula (IV) or a derivative thereof, such as a halide or symmetrical anhydride or mixed anhydride, whereupon the protecting group Z ₁ is replaced by a hydrogen atom under conditions which do not affect the rest of the molecule. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 3, wherein Z represents a group of formula II, in combination with one or more pharmaceutically acceptable substances which are inert or pharmacologically active.